Explorer BK channels affect glucose homeostasis and cell viability of murine pancreatic beta cells

Aims/hypothesis—Evidence is accumulating that Ca2+-regulated K+ (KCa) channels are important for beta cell function. We used BK channel knockout (BK-KO) mice to examine the role of these KCa channels for glucose homeostasis, beta cell function and viability. Methods—Glucose and insulin tolerance were tested with male wild-type and BK-KO mice. BK channels were detected by single-cell RT-PCR, cytosolic Ca2+ concentration ([Ca]c) by fura-2 fluorescence, and insulin secretion by radioimmunoassay. Electrophysiology was performed with the patch-clamp technique. Apoptosis was detected via caspase 3 or TUNEL assay. Results—BK channels were expressed in murine pancreatic beta cells. BK-KO mice were normoglycaemic but displayed markedly impaired glucose tolerance. Genetic or pharmacological deletion of the BK channel reduced glucose-induced insulin secretion from isolated islets. BK-KO and BK channel inhibition (with iberiotoxin, 100 nmol/l) broadened action potentials and abolished the after-hyperpolarisation in glucose-stimulated beta cells. However, BK-KO did not affect action potential frequency, the plateau potential at which action potentials start or glucoseinduced elevation of [Ca]c. BK-KO had no direct influence on exocytosis. Importantly, in BKKO islet cells the fraction of apoptotic cells and the rate of cell death induced by oxidative stress (H2O2, 10–100 μmol/l) were significantly increased compared with wild-type controls. Similar effects were obtained with iberiotoxin. Determination of H2O2-induced K+ currents revealed that BK channels contribute to the hyperpolarising K+ current activated under conditions of oxidative stress. Conclusions/interpretation—Ablation or inhibition of BK channels impairs glucose homeostasis and insulin secretion by interfering with beta cell stimulus–secretion coupling. In addition, BK channels are part of a defence mechanism against apoptosis and oxidative stress.